Strahlentherapie und Onkologie

, Volume 191, Issue 7, pp 566–572 | Cite as

High-grade acute organ toxicity and p16INK4A expression as positive prognostic factors in primary radio(chemo)therapy for patients with head and neck squamous cell carcinoma

  • Narges Tehrany
  • Julia Kitz
  • Margret Rave-Fränk
  • Stephan Lorenzen
  • Li Li
  • Stefan Küffer
  • Clemens F. Hess
  • Peter Burfeind
  • Holger M. Reichardt
  • Martin Canis
  • Tim Beißbarth
  • Hendrik A. WolffEmail author
Original Article



Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT).

Patients and methods

Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16INK4A expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression.


Positivity for HPV DNA (44 samples, 18.9 %) and p16INK4A expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16INK4A expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16INK4A expression and HGAOT, patients with HGAOT only, patients with p16INK4A expression only, and patients without p16INK4A expression or HGAOT, respectively. After multivariate testing p16INK4A expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS.


P16INK4A expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16INK4A expression is particularly important for patients without HGAOT.


Chemoradiotherapy Cyclin-dependent kinase inhibitor 2A Human papilloma virus Acute side effects Prognosis 

Höhergradige akute Organtoxizität und p16INK4A Expression als positiver prognostischer Faktor bei der primären Radio(chemo)therapie für Patienten mit Kopf-Hals-Tumoren



Ein besseres Therapieansprechen von humanen Papillomavirus (HPV)-positiven Kopf-Hals-Tumoren (HNSCC) ist durch Studien belegt. Weniger Beachtung hat bisher die Relevanz unerwünschter Therapienebenwirkungen bei diesem Kollektiv gefunden. Für andere Patientenkollektive ist die Korrelation einer höhergradigen akuten Organtoxizität (HGAOT) mit einem längeren Gesamtüberleben (OS) beschrieben. Wir prüften die Hypothese, dass HPV und HGAOT positive prognostische Faktoren bei Patienten mit HNSCC nach primärer Strahlentherapie oder Radiochemotherapie sind.

Patienten und Methodik

Von 233 Patienten, die mit einer primären Radiotherapie (62 Patienten) oder Radiochemotherapie (171 Patienten) behandelt wurden, standen umfassende klinische Daten und Tumormaterial als Paraffinblöcke zur Verfügung. Der HPV-Nachweis wurde immunhistochemisch als p16INK4A-Expression oder mittels PCR/nested PCR für Virus-DNA geführt. HGAOT wurde als das Auftreten einer Mukositis, Hautreaktion, Dysphagie oder Übelkeit > Grad 2 nach Common Toxicity Criteria definiert. Der Zusammenhang beider Variablen mit dem Gesamtüberleben wurde mittels Cox-Regression analysiert.


In 102 (43,8 %) Tumorgewebeschnitten wurde p16INK4A nachgewiesen, HPV-DNA wurde in 44 Proben gefunden, wobei sich eine signifikante Korrelation zwischen der p16INK4A- und der HPV-DNA-Expression zeigte (p < 0,001). Insgesamt betrug das 5-Jahres-OS 23 %, bei Stratifizierung nach p16INK4A-Expression und dem Auftreten von HGAOT zeigten sich signifikante Abstufungen bezüglich des OS: HGAOT + p16INK4A 47 % OS, nur HGOAT 42 % OS, nur p16INK4A 20 % OS und kein Merkmal 10 % OS – jeweils nach 5 Jahren. Sowohl die p16INK4A-Expression als auch HGAOT waren signifikant mit dem Gesamtüberleben korreliert.


Das Auftreten einer HGAOT ist auch für p16INK4A- bzw. HPV-positive Patienten mit HNSCC ein positiver prognostischer Faktor, wobei akute Organtoxizitäten > Grad 2 mit einem signifikant verlängerten OS korreliert sind.


Radiochemotherapie Cyclin-abhängiger Kinaseinhibitor 2A Humanes Papillomavirus Akute Nebenwirkungen Prognose 



We would like to thank Anke Klages, Judita Wolf-Salgo and Alexandra Bitter for expert technical assistance.

Compliance with ethical guidelines

Conflict of interest

N. Tehrany, J. Kitz, M. Rave-Fränk, S. Lorenzen, L. Li, S. Küffer, C.F. Hess, P. Burfeind, H.M. Reichardt, M. Canis, T. Beißbarth, and H.A. Wolff state that there are no conflicts of interest.

We performed a retrospective study on patient probes (formalin-fixed paraffin-embedded (FFPE) pretreatment tumour tissue) and used patient data. The study was approved as mentioned in “Patients and methods”. Animals were not used.


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Narges Tehrany
    • 1
  • Julia Kitz
    • 2
  • Margret Rave-Fränk
    • 1
  • Stephan Lorenzen
    • 3
  • Li Li
    • 2
  • Stefan Küffer
    • 2
  • Clemens F. Hess
    • 1
  • Peter Burfeind
    • 4
  • Holger M. Reichardt
    • 5
  • Martin Canis
    • 6
  • Tim Beißbarth
    • 3
  • Hendrik A. Wolff
    • 1
    Email author
  1. 1.Department of Radiotherapy and Radiation OncologyUniversity Medical Center GöttingenGöttingenGermany
  2. 2.Department of PathologyUniversity Medical Center GöttingenGöttingenGermany
  3. 3.Department of Medical StatisticsUniversity Medical CenterGöttingenGermany
  4. 4.Institute for Human GeneticsUniversity Medical CenterGöttingenGermany
  5. 5.Institute for Cellular and Molecular ImmunologyUniversity Medical CenterGöttingenGermany
  6. 6.Department of OtorhinolaryngologyHead and Neck Surgery, University Medical Center GöttingenGöttingenGermany

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